Optically active biphenyl derivative and process for optical resolution

ABSTRACT

A biphenyl compound having the formula (I) is newly separated into its optical active compound and useful as an optically separating agent: ##STR1## wherein W, X and Y are each an atom or atomic group selected from among H, F, Cl, Br, I, CH 3 , CF 3 , OH, OCH 3 , NH 2  and N(CH 3 ) 2  and Z is an atom or atomic group selected from among Cl, Br, I, CH 3  and OCH 3 , R is an atomic group having 1 to 20 carbon atoms and containing a polar functional group selected from among ##STR2##

FIELD OF INDUSTRIAL APPLICATION

The present invention relates to a novel optically active biphenylderivative, a process for optical resolution using the same, and aprocess of examining a compound for optical isomer ratios or forabsolute configurations of optically active substances by the use of thesame.

An optically active compound is generally useful as a drug, pesticide,insecticide, herbicide, perfume, ferroelectric liquid crystal, a rawmaterial from which the foregoing is obtained or as a reagent foroptical resolution of another racemate into its optical active compound.

PRIOR ARTS

There have already been known many compounds which have the ability offorming a crystal, preferentially together with either of the opticalisomers of another compound, to thereby resolve the optical isomers(such a compound is hereinafter referred to as the "resolving agent").However, in many cases, the resolving agent and the compound to beresolved therewith must be a combination of a base and an acid (or viceversa).

Recently, it has been ascertained by the inventors of the presentinvention that optically active 2,2'-dihydroxy-1,1'-binaphthyl,10,10'-dihydroxy-9,9'-biphenanthryl and1,6-bis(o-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol have theabove-mentioned ability. However, these resolving agents cannot resolveall compounds and can be applied only to a group of compounds which arelimited in some measure. Therefor, the development of a novel resolvingagent for optical resolution which can be applied to as many compoundsas possible has been needed.

Meanwhile, the determination of the purity of an optically activesubstance as well as the preparation, of an optically active substanceis difficult. A conventional process for this determination involvesusing a chiral shift reagent. This process is characterized by adding acompound which is optically active and has an influence on the chemicalshift of an atom (particularly a proton) present in the neighborhood(such a compound is called "chiral shift reagent") in the NMRspectroscopic analysis of an optically active substance to thereby makethe NMR signals of the optical isomers which ought to appear at the samechemical shift (at the same spectral position) in themselves appear atchemical shifts different from each other and determining the opticalisomer ratio based on the intensities of the signals thus separated. Thechiral shift reagent to be used in the above process generally containsa lanthanide metal such as europium which not only is an expensive raremetal, but also tends to decompose in the presence of water or the like,thus being difficult to handle. Further, the NMR signals are widened bythe influence of the metal to make the discrimination between thesignals difficult, so that the compounds to which such a chiral shiftreagent is applicable are limited. Therefor, the development of a novelchiral shift reagent free from such a metal has been needed.

For the above-mentioned reasons, the present invention aims atdeveloping a novel resolving agent or a novel chiral shift reagent.Needless to say, not all compounds function as a resolving agent or as achiral shift reagent, but as only certain optically active substancescan function as such. Further, there have been no clear guidelines onthe structural features of an optically active substance useful as areagent as described above.

SUMMARY OF THE INVENTION

The inventors of the present invention have intensively studied to solvethe above problems and have found that an optically active biphenylderivative having a proper functional group exhibits excellentperformances as a resolving agent or as a chiral shift reagent. Thepresent invention has been accomplished on the basis of this finding.

Namely, the present invention provides a novel optically active biphenylderivative represented by the general formula (I): ##STR3## wherein W, Xand Y are each an atom or atomic group selected from among H, F, Cl, Br,I, CH₃, CF₃, OH, OCH₃, NH₂ and N(CH₃)₂ and Z is an atom or atomic groupselected from among Cl, Br, I, CH₃ and OCH₃, with the proviso that theatoms represented by H in these alternatives may be either H or D(deuterium); R is an atomic group having 1 to 20 carbon atoms andcontaining a polar functional group selected from among ##STR4##--C.tbd.N and NO₂, wherein preferably all of the carbon atoms except forone or two of them are included in one or two cyclic atomic groups,preferably phenyl or cyclohexyl group(s), and particularly preferably Ris a diarylhydroxymethyl group represented by the formula: --C(OH)Ar₂(wherein Ar is an aromatic group represented by a phenyl group and whichmay have any substituent);

a process for optical resolution using a separating agent containingsaid optically active biphenyl derivative; and a process of examining acompound for optical isomer ratios or for absolute configurations ofoptically active substances by the use of said optically active biphenylderivative as a chiral shift reagent.

The optical activity of the biphenyl derivative according to the presentinvention can be confirmed by the fact that it exhibits opticalrotation. Alternatively, the derivative can be ascertained to beoptically active when the optical isomer ratio is not precisely 1:1, asdetermined by, e.g., liquid chromatography with a separatory column foroptical isomers. Needless to say, it is preferable that the opticalpurity of the derivative to be used as a resolving agent or a chiralshift reagent be as high as possible.

Although the biphenyl derivative of the present invention may beprepared by any process, it can be relatively easily prepared bychemically replacing the substituents of a known optically activebiphenyl derivative. For example,4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl can beprepared by reacting 4,4',6,6'-tetrachlorobiphenyl-2,2'-dicarboxylicacid with a phenyl Grignard reagent to replace the carboxyl groups withdiphenylhydroxymethyl groups.

Optical resolution using the biphenyl derivative of the presentinvention as a resolving agent may be conducted in any manner.Preferably, it is conducted through the formation of a clathratecompound of the resolving agent with a compound to be resolved. As willbe described in relation to the utilization of the derivative as achiral shift reagent, however, the derivative exhibits differentinteractions on the optical isomers of the compound to be resolvedrespectively, not only in a crystal structure but also in a solution.Accordingly, it is apparent that the resolving power of the derivativeis exhibited not only in the above process through the formation of theclathrate compound. For example, the optical resolution according to thepresent invention may be conducted by liquid or gas chromatography usingthe derivative chemically or physically immobilized on a support as apacking. Further, in the process through the formation of a crystal ofthe derivative with the compound to be resolved, the formation of thecrystal and the isolation of the objective compound from the crystal maybe each conducted by any method.

When the biphenyl derivative of the present invention is used as achiral shift reagent, the compound to be examined for optical purity isdissolved in a proper solvent (generally so as to give several steps ofconcentrations), followed by the addition of a proper amount of a chiralshift reagent. When the obtained solution is subjected to NMRspectroscopic analysis, in many cases, one peak (or one set of peaks),which is exhibited in a case wherein no chiral shift reagent iscontained, is split into two peaks (or two sets of peaks), which areassignable to optical isomers respectively. The optical purity can becalculated from the area intensities of the peaks. Further, thepositions of the peaks can be experimentally correlated with thestructures (absolute configurations) of the optical isomers.

EXAMPLE

The present invention will now be described in more detail by referringto the following Examples, though it is needless to say that the presentinvention is not limited to them.

EXAMPLE 1

4,4',6,6'-Tetrachlorobiphenyl-2,2'-dicarboxylic acid was opticallyresolved according to the diastereomer method described in E. R.Atkinson, Org. Prep. Proced. Int., 3, 71 (1971). The obtained opticallyactive substance was treated with phenylmagnesium bromide to giveoptically active4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl.

The physical properties of the raw material and the product are givenbelow.

    ______________________________________                                        Raw material Product                                                          angle of     angle of rotation [α].sub.D                                                            m.p.                                              rotation     (c = 0.1, chloroform)                                                                        (°C.)                                      ______________________________________                                        +            +110°   231 to 233                                        -            -110°   231 to 233                                        ______________________________________                                    

EXAMPLE 2

1.5 g of(+)-4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl and0.45 g of 3-methyl-2-pyrrolidone (racemic mixture) were dissolved in 6ml of a benzene-hexane mixture having a volume ratio of 1. The obtainedsolution was allowed to stand at a room temperature for 24 hours to givea complex of(+)-4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl with3-methyl-2-pyrrolidone (1:1) as a colorless crystal. This crystal wasrecrystallized five times to give 1.12 g of a pure crystal [m.p.: 213°to 214° C., [α]_(D) +87.7° (c=0.1, chloroform)]. This pure crystal washeated in a vacuum to give 0.14 g of (-)-3-methyl-2-pyrrolidone [[α]_(D)-60.6° (c=0.3, benzene), optical purity: 100% e.e., yield: 62%]. On theother hand, the mother liquor of the recrystallization gave 0.25 g of(+)-3-methyl-2-pyrrolidone (47% e.e.).

EXAMPLE 3

The (+)-3-methyl-2-pyrrolidone (47% e.e.) prepared in Example 2 and(-)-4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl weretreated in a similar manner to that of Example 2 to give a complex (1:1)as a crystal. This crystal was further treated in a similar manner tothat of Example 2 to give 0.1 g of (+)-3-methyl-2-pyrrolidone [[α]_(D)+60.6° (c=0.3, benzene), 100% e.e.].

EXAMPLE 4

The NMR chemical shifts of various racemic mixtures (samples) listed inTable 1 were measured in deuteriochloroform by using(+)-4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl(hereinafter abbreviated to "Optically active substance 1") as a chiralshift reagent. The measurement was conducted by using a solutioncontaining 0.02 g of a sample per ml of deuteriochloroform with respectto a case wherein no optically active substance 1 was contained andcases wherein it was contained in an amount of 1 or 2 mol per mol of thesample, thus determining the chemical shift of the proton represented initalic type in the structural formula of the sample. The results aregiven in Table 1.

                  TABLE 1                                                         ______________________________________                                        Relationship between chemical shift and molar                                 amount of Optically active substance 1                                                       Chemical shift (ppm)                                                          molar ratio of Optically active                                               substance 1 to sample                                          Sample           0         1         2                                        ______________________________________                                         ##STR5##        1.377     1.234 1.251                                                                             1.065 1.096                               ##STR6##        1.038     0.979 1.000                                                                             0.938 0.983                               ##STR7##        1.196     1.081 1.100                                                                             0.958 1.017                               ##STR8##        1.220     1.033 1.058                                                                             0.956 0.998                               ##STR9##        4.860     4.779     4.635 4.676                               ##STR10##       4.605     4.295 4.441                                         ##STR11##       1.552     1.467 1.483                                                                             1.407 1.440                              n-OctSOCH.sub.3  2.550     2.227                                                                         2.280                                               ##STR12##       2.853     2.623 2.667                                         ##STR13##       2.703     2.444 2.500                                        p-TolSeOCH.sub.3 2.587     2.167                                                                         2.283                                               ##STR14##       3.483     2.910 2.943                                                                             2.743 2.813                               ##STR15##       1.643 3.588                                                                             1.414 1.432 3.430 3.450                                                                 1.313 1.336 3.335 3.365                   ##STR16##       1.928     1.610 1.661                                        PhAsOCH.sub.3    1.807     1.433     1.204                                                               1.457                                                                         1.329                                              ______________________________________                                         note)                                                                         Ph represents a phenyl group, Me represents a methyl group, iPr represent     an isopropyl group, nOct represents a noctyl group and pTol represents a      ptolyl group.                                                            

As is apparent from the results given in Table 1, one chemical shiftexhibited in a case wherein no optically active substance 1 was addedwas split into two chemical shifts by the addition of optically activesubstance 1.

I claim:
 1. An optically active biphenyl derivative represented by thegeneral formula (I): ##STR17## wherein W, X and Y are selected fromamong H, F, Cl, Br, I, CH₃, CF₃, OH, OCH₃, NH₂ and N(CH₃)₂ and Z isselected from among Cl, Br, I, CH₃ and OCH₃ ; R is a group having 1 to20 carbon atoms and containing a polar functional group selected fromamong ##STR18##
 2. An optically active biphenyl derivative as set forthin claim 1, wherein R is a diarylhydroxymethyl group represented by theformula: --C(OH)Ar₂, wherein Ar is an aromatic group.
 3. An opticallyactive biphenyl derivative as set forth in claim 1, wherein R is adiarylhydroxymethyl group represented by the formula: --C(OH)Ar₂,wherein Ar is an aromatic group, Z and X are each Cl, and W and Y areeach H.
 4. An optically active biphenyl derivative as set forth in claim2, wherein Ar is an aromatic group comprising a phenyl group.
 5. Anoptically active biphenyl derivative as set forth in claim 2, wherein Aris a phenyl group.
 6. An optically active biphenyl derivative as setforth in claim 1, wherein said derivative is4,4',6,6'-tetrachloro-2,2'-bis(hydroxydiphenylmethyl)biphenyl.
 7. Anoptically active biphenyl derivative as set forth in claim 3, wherein Aris an aromatic group comprising a phenyl group.
 8. An optically activebiphenyl derivative as set forth in claim 3, wherein Ar is a phenylgroup.
 9. An optically active biphenyl derivative as set forth in claim2, wherein Ar is an aromatic group selected from the group consisting ofa phenyl group and a substituted phenyl group.
 10. An optically activebiphenyl derivative as set forth in claim 3, wherein Ar is an aromaticgroup selected from the group consisting of a phenyl group and asubstituted phenyl group.